1. Field of the Invention
The invention relates generally to the field of immunobiology. In particular, the invention relates to compositions and methods useful in stimulating an NKT cell or enhancing an immune response against a disease or disorder.
2. Introduction
Lipid species are ubiquitous constituents of all eukaryotic membranes and pathogenic microorganisms. Despite the abundance of lipids in biological systems, the anti-lipid immune response has not been studied to the same extent as the anti-peptide response. For example, comparatively little is known about the phenomenon of non-toll-like receptor (non-TLR) recognition of lipid antigens. Unlike peptide antigens, lipids are processed and presented to the immune system by the CD1 family of β2 microglobulin-associated molecules. In contrast to class I and II major histocompatibility complex (MHC) molecules that present peptide antigens to CD8+ and CD4+ T cells, respectively, CD1 molecules have evolved to capture and process both foreign and self lipid antigens for display to particular subsets of T cells.
A variety of lipids with different structures have been shown to bind CD1 molecules in a unique manner that accommodates a fatty acid chain in each of the two hydrophobic binding pockets (A′ and F) of the CD1 molecule. Lipid species capable of binding CD1 molecules include mycolic acids, diacylglycerols, sphingolipids, polyisoprenoids, lipopeptides, phosphomycoketides and small hydrophobic compounds.
The CD1 presentation pathway triggers both innate and adaptive immune responses by activating two complementary CD1-restricted T cell subsets: NKT cells that perform adjuvant functions, and non-NKT T cells capable of helper or cytolytic functions.
NKT cells, which express both natural killer (NK) cell surface markers and a conserved, semi-invariant T-cell receptor (TCR), Vα14-Jα18/Vβ8 in mice and Vα24-Jα18/Vβ11 in humans, are characterized by self lipid reactivity and rapid effector responses. Accordingly, NKT cells play an important role in a number of immune functions, including antimicrobial responses, antitumor immunity and regulation of the balance between tolerance and autoimmunity.
The apparent pluripotency of NKT cells depends specifically on their ability to interact with dendritic cells (DCs), to determine the TH1 or TH2 polarity of the T cell response, and to initiate T cell anergy in appropriate circumstances. The maturation and recruitment process of DCs is central to their function. Indeed, DCs can rapidly progress from quiescence and low metabolic activity to active uptake of antigen, processing and tissue migration after receiving differentiation signals.
A number of natural and synthetic lipid molecules are processed by DCs and presented by CD1 molecules to NKT cells. The prototypical compound used to study NKT cell activation in vitro and in vivo is KRN7000, an α-galactosylceramide (“αGalCer”) derived from marine sponge Agelas mauritianus. Additional agonists include isoglobotrihexosylceramide (“iGb3” or “PBS-47”), which is an endogenous glycosphingolipid, as well as members of a class of microbial-derived α-glycuronosylceramides. However, very little has been elucidated regarding anti-lipid responses in general. In the context of vaccination in particular, even less is known regarding the mechanism of lipid adjuvanticity.
Adjuvants are used to augment the immune response in anti-microbial and anti-tumor vaccination protocols, as well as in experimental immunology. The chemical nature of adjuvants, their mechanisms of action and their side effect profiles are highly variable. In some cases, side effects can be ascribed to an inappropriate immune response, or in other cases, can be the result of adverse pharmacological reactions. At present, the choice of adjuvant for human vaccination reflects a compromise between the requirement for adjuvanticity and an acceptable level of side effects.